Increased numbers of fibroblasts are a key feature of pulmonary fibrosis, and their coalescence in densely populated cell formations, termed fibroblastic foci, is a diagnostic histopathological feature of idiopathic pulmonary fibrosis (IPF). Increased proliferation is a likely mechanism for this increase in fibroblasts whose phenotype is distinct from cells isolated from normal lung. Interestingly a new fibroblast phenotype is found to emerge in animal models of lung injury and fibrosis characterized by the expression of telomerase activity. While telomerase activity is associated with increased proliferative capacity and life span in certain cells during early development and many tumor cells, its significance in the pathogenesis of pulmonary fibrosis is unknown. In this project it is hypothesized that emergence de novo of a telomerase-expressing fibroblast phenotype is induced by certain factors resulting in increased cell proliferation and/or survival. This would increase the pool size of proliferative cells serving as an intermediate differentiated population that can terminally differentiate to the myofibroblast phenotype.
Four specific aims are proposed to test this hypothesis. First, the mechanism of telomerase induction will be studied in lung fibroblasts. The telomerase gene and its 5'-flanking sequences will be cloned for analysis of transcriptional regulation. Second, the relationship between the telomerase expressing and myofibroblast phenotypes will be examined by analyzing the relationship between telomerase and (-smooth muscle actin gene expression, and whether the transcriptional regulatory mechanisms for both genes are somehow related in a functionally meaningful way in terms of cellular differentiation. Third, the functional significance of telomerase expression will be analyzed by comparing telomere length with telomerase expression in vivo and in vitro, and whether telomerase expression endow cells with differential characteristics with respect to response to growth factors and/or apoptotic signals. Finally, the role of telomerase in pulmonary fibrosis will be examined in vivo in the bleomycin model by use of telomerase (either telomerase reverse transcriptase or telomerase RNA component) knockout mice as well as specific telomerase inhibitors. By using these combined approaches, new insights into the potential role and significance of this telomerase expressing phenotype will be uncovered, which may prove to be useful for devising future novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077297-04
Application #
7247939
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
2004-07-05
Project End
2009-03-31
Budget Start
2007-07-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$353,343
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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